7, 8-dihydro-3&#39;, 4&#39;-disubstituted cyclohexeno-(1&#39;, 2&#39;:14, 8)-codeinones



United States Patent 3,329,682 7,8-DIHYDRO-3',4-DISUBSTITUTED CYCLO- HEXENO-(1',2':14,8)-CODEINONES Kenneth W. Bentley, Willerby, England, assignor to Reckitt & Sons Limited, Dansom Lane, England, a British company No Drawing. Filed July 7, 1965, Ser. No. 470,249 Claims priority, application Great Britain, July 8, 1964, 28,156/ 64 11 Claims. (Cl. 260--285) The invention relates to novel derivatives of codeine and morphine and to processes for their manufacture.

More particularly, the present invention provides compounds of the formula wherein R represents a hydrogen atom or a methyl group,

R represents a methyl, ethyl, propyl or aryl group,

R represents a hydrogen atom, an alicyclic group with 4, 5 or 6 carbon atoms, an aryl or tetrahydrofurano group, an alkyl or alkenyl group containing up to 7 carbon atoms, or an alkyl or alkenyl group containing up to 7 carbon atoms substituted on any of carbon atoms 1 to 4 by an alicyclic, aryl, alkoxy, aryloxy, morpholino or tetrahydrofurano group, provided that R represents a hydrogen atom only when R represents an aryl group,

R represents an alkyl or alkenyl group with up to about 8 carbon atoms, optionally substituted on carbon atoms 1 to 5 by an alkyl, aryl, alicyclic or heterocyclic group.

R represents a single oxygen atom forming part of a carbonyl group or a hydrogen atom and an oxygen atom forming part of a secondary alcoholic group or a derivative thereof, and

R represents an aryl group, and salts of bases of the above formulae with pharmaceutically acceptable acids.

The compounds of the invention are therapeutically useful on account of their power to alfect the central nervous system, particularly on account of their depressant, analgesic, sedative, antitussive and/ or transquilizing elfects.

The present invention also includes a process for the preparation of the novel compounds of the invention in 3,329,682 Patented July 4, 1967 which R is an oxygen atom wherein an alcohol of the structure:

in which R, R R and R have the meanings given above is heated with 5-10 N hydrochloric acid, or if R is a hydrogen atom, by heating an alcohol of the structure given above in which R is a methyl group with concentrated hydrobromic acid.

Compounds of this structure are described in British Patents 925,723, 937,214 and 969,263.

The invention also includes a process for the preparation of bases of the structure given above, in which R represents a hydrogen atom and a hydroxyl group, wherein the ketonic bases in which R is a single oxygen atom are reduced with sodium borohydride or other complex hydride.

The invention further includes a process for the preparation of bases of the structures given in which the group R is other than hydrogen, wherein the bases in which R is hydrogen are heated with the corresponding halide R Cl, R Br or R 1, and also a process for the preparation of such bases in which R is a hydrogen atom and a hydroxyl group wherein the secondary base is acylated with an acid halide and the resulting amide reduced with lithium aluminum hydride.

The compounds according to the invention have a basic skeleton that has not previously been described in the literature. One compound according to the invention is shown here in order to illustrate the nomenclature and the numbering of the various substituents 7,8-dihydro-3' ethyl 4 methylcyclohex 3 eno- (1,2': 14,8 -codeinone.

3,329,682 3 The compounds according to the invention ere the bases do not contain the system --CH=CH. Only originally ascribed the erroneous structure: the bases derived from the methyl aryl carbinols, containing the system no HOC-Aryl CH; contain a double bond bearing any hydrogen and this 0 L 3 is present as the system CH=CAryl.

The acid catalyzed rearrangement of the alcohols is 10 now seen to involve a proton addition-abstraction R equilibrium between the alkenylcodeinones (K) and (M) by way of the protonated intermediate (L). This is shown in the following sequence:

s In 2 J 1 H01; \CH2R2 R 2 R R I v n (L) a (J) (K) o wherein R, R R R and R have the meanings given above, the cyclopenteno ring being formed by the following rearrangement;

The subsequent cyclization of (M)E(N) to (P) is essentially the same process as was originally envisaged in the cyclization of (G) to (I) and presumably steric (a) (F) (G) a H H H f 0 a o e) a a a R a (I) Q (it) However, extensive spectral studies have revealed the necessity of revision of these structures, and in particular nuclear magnetic resonance studies have revealed that 75 factors favor formation of the six-membered ring rather than a five-membered ring. It may be noted that, in the case where R is a hydro- MeO addition-extraction equilibrium (K)S(L)2(M), namely where R =H and R an aryl group and in this case an appreciable quantity of both isomers (K) and (M) presumably exists at equilibrium, (M) being selectively removed by cyclization to (P).

From these results it becomes a simple matter to determine the nature of the final product of rearrangement of a particular alcohol:

o Me

I CMe El:

E0 OHzEt o Et Et 0H3 I CMe Ph HO CHzPh o Ph I CPh Ph 110 CHzPh 1 0 ony qp1 Ph Ph HO/ CHaPh It will also be noted that the group CH R in the initial alcohol is essential for this rearrangement to proceed as shown above. In the case of, for example, the cyclohexyl car-binol. (Q) rearrangement of this type could give only the ketone (V) and the analogous cyclopentyl and isopropyl carbinols could only behave in this way. However, in these cases steric factors apparently prevent the sequence;

involving the formation of the six-membered ring with the gem-disubstituted carbon atom, and alcohols of this type either rearrange only as far as the 14-substituted codeinone or undergo simple dehydration without ring opening.

In the case where the carbonium ion (0) has R =H and R =aryl, loss of a proton in the direction shown in .(O) is not specially favored by hyperconjugation effects .as it is in all the other cases, with the result that such carbonium ions lose a proton in both possible ways, giving rise to bases having double bonds in both possible positions, i.e. having both possible structures (A) and (B).

The invention is further illustrated by the following examples in which parts are parts by weight.

EXAMPLE 1 7,8-dihydro-3-mwthyl-4-methylcyclohex-3'-en0 (1',2:14,8)-codein0ne 6,14-endoetheno-7-(2-hydroxy 2 butyl)-tetrahydro thebaine (10 parts) was heated on a water bath for 2 hours.

with 5 N hydrochloric acid and the mixture was cooled and diluted with water. The sparingly soluble hydrochloride (M.P. 284 C.) was collected and dissolved in aqueous ethanol, from which solution the base, M.P. 196 C. 8 parts) was precipitated with sodium hydroxide. It was obtained as white prisms (M.P. 199 C., 1 max. 1725 cmf on recrystallization from ethanol. Found: C, 76.1%; H, 7.9%. C H O N requires: C, 76.0%; H, 7.7%.

. EXAMPLE 2 7,8-dihydr0-3-m'ethyl-4'-methylcyclohex-3'-en0 (1,2:14,8)-c0deine The base from Example 1 (5 parts) was reduced with sodium borohydride (0.5 part) in ethanolic solution. The product was precipitated from solution by the addition of water and, when collected and recrystallized from aqueous ethanol, it had M.P. 143 C. Found: C, 72.0%; H, 8.4%. C H O N.H O requires: C, 72.2%; H, 8.3%.

EXAMPLE 3 7,8-dihydro-3'-ethyl-4-methylcycl0hex-3'-en0 (1,2':14,8)-c0deinone 6,14-endoetheno-7-(2-hydroxy 2 pentyl)-tetrahydrothebaine (10 parts) was heated on a water bathfor 2 7,8-dihydro-3'-ethyl-4-methylcycl0hex-3-en0 (1',2':14,8)-c0deine The base from Example 3 (5 parts) was reduced with sodium borohydride (0.8 part) in hot ethanol. The product (5 parts) was precipitated with water, collected and recrystallized from aqueous ethanol, and was obtained as white needles, M.P. 166 C. Found: C, 75.7%; H, 8.4%. C H O N requires: C, 76.1%, H, 8.4%.

EXAMPLE 5 6,14-endoetheno-7-(Z-hydroxy 2 pentyl)-tetrahydronorthebaine (5 parts) was heated at 100 C. with 5 N hydrochloric acid for 2 hours. The resulting hydrochloride (M.P. 300 C.) gave the base (3.5 parts) when treated with ammonia. After recrystallization from ethanol it had M.P. 210 C., 11 max. 1730 CIILTI. Found: C, 75.8%; H, 7.9%. C H O N requires: C, 76.0%; H, 7.7%.

EXAMPLE 6 The base, M.P. 120 C. (found C, 75.7%; H, 8.0%. C H O N. /2H O requires: C, 75.7%; H, 8.0%) was prepared as described in Examples 1, 3 and 5 by the rearrangement of N-allyl-6,14-endoetheno-7-(2-hydroxy-2- pentyl)-tetrahydronorthebaine under the influence of hydrochloric acid. The hydrochloride had M.P. 246 C.

EXAMPLE 7 7,8-dihydr-3'-ethyl-4'-methylcycl0hex-3-en0 (1,2':14,8)-m0rphin0-ne (a) 6,l4-endoetheno-7-(2-hydroxy 2 pentyl)-tetrahydrothebaine (5 parts) was boiled under reflux for 1 hour with concentrated aqueous hydrobromic acid, the mixture was cooled and diluted with water and the base was precipitated by ammonia. After recrystallization from aqueous 2-ethoxyethanol, it was obtained as cream colored plates of M.P. 110 C. Found: C, 73.0%; H, 8.0%. C H O N.H O requires: C, 72.6%; H, 8.3%. 11 max. 1730 cmf Yield 3 parts.

(b) The same material was obtained by the rearrangement of 6,14-endoetheno-7-(2-hydroxy-2-pentyl)-tetrahydrooripavine under the influence of concentrated hydrochloric acid in accordance with the general method of Example 1.

EXAMPLE 8 7,8-dihydr0-3'ethyl-4-methylcycl0hex-3-en0 (1 ',2:14,8) -m'orphine The base of Example 7 (5 parts) was reduced with sodium borohydride (0.8 part) in hot ethanol. The base was precipitated with water, collected and recrystallized from benzene/ light petroleum, when it was obtained as a white, amorphous powder. Found: C, 74.8%; H, 8.3%.

. 24 a1 a requires: C, 75.5%; H, 8.2%.

EXAMPLE 9 7,8-dihydro-3-p*r0pyl-4'-methylcyclohex-3-eno (1 ,2:14,8)-c0deinone This base was prepared as in Example 1 from 6,14- endoetheno-7-(2-hydroxy 2 hexyl)-tetrahydrothebaine 8 and concentrated hydrochloric acid. On recrystallization from aqueous ethanol it was obtained as prisms of M.P. 144 C. Found: C, 76.5%; H, 8.2%. C H O N requires: C, 76.8%; H, 8.5%. '7 max. 1730 cmf Hydrochloride M.P. 260 C.

EXAMPLE 10 Prepared as in Example 1 from 6,14-endoetheno-7-(2- hydroxy-5-methyl-2-hexyl)-tetrahydrothebaine and concentrated hydrochloric acid, this base was obtained as white prisms of M.P. 195 C. Found: C, 76.5%; H, 8.3%. C H O N requires: C, 76.7%; H, 8.2%. 7 max. 1730 cm.- hydrochloride M.P. 254 C.

EXAMPLE ll 7,8-dihydr0-34sobutyl-4'-m'ethylcyclohex-3- en0(1 ,2:14,8)-coaeine This base was obtained by the sodium borohydride reduction of the base of Example 10. On recrystallization from aqueous ethanol it was obtained as needles, M.P. 184 C. Found: C, 76.5%; H, 8.9%. c2'1H3'1O3N requires: C, 76.3%; H, 8.7%.

EXAMPLE 12 N cyano 6,14 endoetheno 7 (2 hydroxy 2- pentyl)-tetrahydronorthebaine (12.2 g.) was treated with concentrated hydrochloric acid m1.) at room temperature for 18 hours, The product was precipitated with water, collected, washed with hot ethanol and dried (10.5 g.). M.P. 277279 C. (Found: C, 74.8; H, 7.0; N, 7.0%. C H N O requires: C, 74.2; H, 7.0; N, 6.9%.) 7 max. 1730 61117 EXAMPLE l3 This was prepared from N-cyano-6,l4-endoetheno-7- (2-hydroxy-2-hexyl)-tetrahydronorthebaine by the method of Example 12. The product was precipitated with water, collected, recrystallized from ethanol, washed with hot petroleum ether (B.P. 6080 C.) and further recrystallized from ethanol. M.P. 218219 C. (Found: C, 73.8; H, 7.1; N, 6.8%. C H N O requires: C, 74.6; H, 7.2; N, 6.7%.) 7 max. 1730 cmf EXAMPLE 14 This was prepared from N-cyano-6,14-endoetheno-7- (2-hydroxy-2-butyl)tetrahydronorthebaine by the method of Example 12. The product was precipitated with water, collected and recrystallized with methanol. M.P. 265-272" C. (Found: C, 73.4; H, 6.7%. C H N O requires: C, 73.8; H, 6.7%.) '7 max. 1730 cmf EXAMPLE 15 N-cyano-7,8-dihyriro-3'-n-butyl-4'-methylcyclohex- 3 '-en0(1 ',2':14,8 -n0rcodein0ne This was prepared from N-cyano-6,14-endoetheno-7- (2-hydroxy-2-heptyl)-tetrahydronorthebaine by the method of Example 12. The product was precipitated with water, collected, recrystallized from ethanol and washed with hot petroleum ether (B.P. 6080 C.). M.P. 202- 205 C. (Found: C, 74.9; H, 7.4; N, 6.4%. C H N O requires: C, 75.0; H, 7.5; N, 6.5%.) 7 max. 1735 GEL-1.

This was obtained from Ncyano-6,14-endoethen ;7- (2 hydroxy 5 methyl 2 hexyl) tetrahydronorthebaine by the method of Example 12. The product was precipitated with water, collected, recrystallized from ethanol and Washed with hot petroleum ether (B.P. 6()80" C.). M.P. 223-225 C. (Found: C, 75.0; H, 7.5; N, 6.6%. C H N O requires: C, 75.0; H, 7.5; N, 6.5%.) 7 max. 1730 cmr EXAMPLE 17 The base from Example 12 (37.5 g.), water (1400 ml.), 2-ethoxyethanol (600 ml.) and potassium hydroxide (144 g.) were boiled under reflux with stirring for 18 hours. After cooling, the crude product (23.5 g.) was collected and recrystallized from aqueous ethanol. M.P. 210-215 C. (Found: C, 76.5; H, 7.8; N, 3.7%. C I-I NO requires: C, 76.0; H, 7.7; N, 3.7%.) 7 max.

1725 cmf EXAMPLE 18 The base from Example 13 (30 g.), Water (840 ml.), 2-ethoxyethanol (420 ml.) and potassium hydroxide (120 g.) were boiled under reflux for 18 hours. The product was precipitated with iced water (3500 ml.) and collected. The crude nor-compound (27 g.) was used without further purification for the alkylation reactions in Examples 25, 26 and 28.

EXAMPLE 19 EXAMPLE 20 The base from Example 17 g.), methylallyl chloride (1.5 g.), anhydrous potassium carbonate g.) and methyl ethyl ketone (75 ml.) were boiled under reflux with stirring for 18 hours. The material (4 g.) obtained by filtration and evaporation contained much unreacted nor-compound and was treated further in boiling methyl ethyl ketone (75 ml.) with Z-methylallyl chloride (2.5 g.) and anhydrous potassium carbonate (10 g.) for 18 hours. The mixture was filtered, the filtrate evaporated to dryness and the product recrystallized from aqueous methanol (1.4 g.). M.P. 126129 C. (Found: C, 77.6; H, 8.1; N, 3.2%. C H NO requires: C, 77.6; H, 8.1; N, 3.2%.) 7 max. 1730 cmf EXAMPLE 21 This was obtained from the base from Example 17 (4.6 g.), 3:3-dimethylallyl bromide (3.2 g.), anhydrous potassium carbonate (9 g.) and acetone (100 ml.) by the method of Example 19. The product was recrystallized from aqueous ethanol. M.P. 109-113" C. (Found: C, 77.7; H, 8.4; N, 3.2%. C H NO requires: C, 77.8; H, 8.3; N, 3.1%.) 7 max. 1730 cm.-

1 0 EXAMPLE 22 This was obtained from the base from Example 17 (2.3 g.), butyl iodide (6 g.), anhydrous potassium carbonate (5 g.) and acetone ml.) by the method of Example 19. The product was purified by chromatography through an alumina column eluting with benzene petroleum ether (B.P. -80 C.). M.P. 123-124 C. (Found: C, 77.2; H, 8.6; N, 3.2%. C H NO requires: C, 77.2; H, 8.6: N. 3.2%.) 7 max. 1735 cm.-

EXAMPLE 23 This was obtained from the base from Example 17 (2 g.), hexyl bromide (5 g.), anhydrous potassium carbonate (4 g.) and acetone (50 ml.) by the method of Example 19. The product was purified by chromatography through an alumina column eluting with benzene petroleum ether (B.P. 6080 C.). M.P. 129-131 C. (Found: C, 77.5; H, 9.0; N, 3.1%. C H NO requires: C, 77.7; H. 8

N, 3.0%.) 'ymax. 1735 cmf EXAMPLE 24 This was obtained from the base from Example 17 (4.5 g.), n-octyl bromide (11.3 g.), anhydrous potassium carbonate (9 g.) and acetone (75 ml.) by the method of Example 19. The product was purified by chromatography through an alumina column eluting with benzene petroleum ether (B.P. 6080 C.). M.P. 103.5104 C. (Found: C, 78.3; H, 9.3; N, 3.0%. C H NO requires: C, 78.2; H, 9.2; N, 2.8%.) 7 max. 1730 cmf EXAMPLE 25 N-allyl-7,8-dihydr0-3'-n-propyl-4'-methylcyclohex- 3'-en0(1 ',2':14,8 -n0rc0dein0ne This was obtained from the crude base from Example 18 (8 g.), allyl bromide (5 g.), anhydrous potassium carbonate (16 g.) and acetone (100 ml.) by the method of Example 19. The product was purified by chromatography through an alumina column eluting with benzene petroleum ether (B.P. 60-80 C.). M.P. approx. 60 C. (Found: C, 76.9; H, 8.1; N, 3.3%. C H NO requires: C, 77.6; H, 8.1; N, 3.2%.) Hydrochloride M.P. 139142 C. 7 max. 1735 cmf EXAMPLE 26 The crude base from Example18 (8 g.), 2-methylallyl chloride (4 g.), anhydrous potassium carbonate (16 g.) and acetone ml.) were boiled under reflux for 18 hours. The material (7 g.) obtained by filtration and evaporation contained much unreacted nor-compound and was further treated with 2-methylallyl chloride (6 g.) anhydrous potassium carbonate (14 g.) and acetone (100 ml.) for 18 hours. The mixture was filtered, the filtrate evaporated to dryness and the product purified by chromatography through an alumina column eluting with benzene petroleum ether (B.P. 60-80 C.). M.P. approx. 50 C. (Found: C, 77.4; H, 8.3; N,3.2%. C H NO requires: C, 77.8; H, 8.3; N, 3.1%.) Hydrochloric M.P. 128-132 C. 'y max. 1725 cmf EXAMPLE 27 N-ethyl-7,8-dihydro-3'-n-propyl-4'-methylcyclohex- 3'-en0(1',2':14,8) -norcodein0ne This was obtained from the crude base from Example 18 (5 g.), ethyl iodide (5 g.), anhydrous potassium car- 11 bonate (10 g.) and acetone (50 ml.) by the method of Example 19. The product was purified by chromatography through an alumina column eluting with benzene petroleum ether (B.P. 60-80 C.). M.P. approx. 50 C. (Found: C, 76.8; H, 8.5; N, 3.5%. C27H35NO3 requires: C, 76.9; H, 8.4; N, 3.3%.) Hydrochloride M.P. 142l45 C. 'y 1720 CIIIII.

EXAMPLE 28 This was obtained from the crude base from Example 18 (4.4 g.), propyl iodide (5 g.), anhydrous potassium carbonate (10 g.) and acetone (50 ml.) by the method of Example 19. The product was purified by chromatography through an alumina column eluting with benzene petroleum ether (B.P. 60-80 C). M.P. approx. 50 C. (Found: C, 77.3; H, 8.6; N, 3.4%. C H NO requires: C, 77.2; H, 8.6; N, 3.2%.) Hydrochloride M.P. 140144 C. 'y max. 1730 cmf EXAMPLE 29 N-ally1-6,14-endoetheno-7-(2 hydroxy 5 methyl 2- hexyl)-tetrahydronorthebaine (3.1 g.) was treated at room temperature with concentrated hydrochloric acid (15 ml.) for 42 hours. The product was precipitated with water (50 ml.), collected, and basified with aqueous ammonia (1.9 g.). The product was purified by chromatography through an alumina column eluting with benzene petroleum ether (B.P. 6080 C.). M. P. indefinite. Found: C, 78.3; H, 8.4; N, 3.1%. C29H37NO3 requires: C, 77.8; H, 8.3; N, 3.1%.) Hydrochloride M.P. 140-144" C. 7 max. 1725 cmf EXAMPLE 3 N-ethyl-6,14-endoetheno-7-(2-hydroxy methyl 2- hexyl)tetrahydronorthebaine hydrochloride (9 g.) was treated at room temperature with concentrated hydrochloric acid (50 ml.) for 66 hours. The mixture was diluted with water (600 ml.) and the gummy precipitate removed. The product was precipitated from the mother liquors by basification with ammonia. The product (3.5 g.) was purified by chromatography through an alumina column eluting with benzene petroleum ether (B.P. 60- 80 C.). M.P. approx. 65 C. Hydrochloride M.P. 142- 146" C. 7 max. 1725 cm.-

EXAMPLE 3 l N-cyclopropylmethyl-6,l4-endoethen-o-7-(2-hydroxy 2- butyl-tetrahydronorthebaine (2.5 g.) was treated at room temperature with concentrated hydrochloric acid (25 ml.) for 66 hours. The mixture was diluted and basified, the product collected and recrystallized from aqueous methanol. M.P. 137l40 C. (Found: C, 77.7; H, 8.0; N, 3.3%. C27H33NO3 requires: C, 77.3; H, 8.0; N, 3.3%.) 7 max. 1730 cmf EXAMPLE 32 A mixture of the base from Example 19 (2.9 g.), sodium borohydride (0.61 g.) and ethanol (20 ml.) was boiled for 2 hours, evaporated to dryness. The residue was taken up in cold aqueous dilute hydrochloric acid and basified with aqueous ammonia. The product (2.5 g.) was collected and purified by chromatography through an alumina column, eluting with benzene petroleum ether (B.P.

6080 C.). M.P. approx. 45 C. (Found: C, 75.5; H, 8.3; N, 3.4%. C27H35NO3 requires: C, 76.9; H, 8.4; N, 3.3%). No carbonyl band at approx. 1730 cmr Hydrochloride M.P. 143-145 C.

EXAMPLE 33 EXAMPLE 34 6,14 endoetheno 7 (3-hydroxy-3-pentyl)tetrahydrothebaine was heated on a water bath for 1 hour with cone. HCl. The product was obtained. The product was precipitated by basification with ammonia (sp. gr. 0.88), collected and recrystallized from ethanol. M.P. 198 C. (Found: C, 76.2; H, 8.1%. C H NO requires: C, 76.4; H, 8.0%.) 7 max. 1730 cmf EXAMPLE 3 5 6,14 endoetheno 7 (1-hydroxy-1-phenyl-1-propyl)- tetrahydrothebaine (2 g.) was heated on a water bath for 1 hour with concentrated hydrochloric acid (50 ml.). The mixture was diluted with Water. Ethanol was added to dissolve the viscous hydrochloride, and the aqueous ethanolic solution, basified with ammonia. The precipitated base was collected, washed with water and recrystallized from 2-ethoxyethanol. M.P. 224-226 C. '7 max. cm.-

EXAMPLE 36 7,8-dihydr0-3-pr0pyl-4-phenylcycl0hex-3-en0 (1 ',2:14,8 -m0rphinone Prepared as in Example 35 from 6,14-endoetheno-7,(2-

hydroxy-2-hexyl)-tetrahydrooripavine. M.P. 114115 C. Hydrochloride M.P. 248-250 C. (dec.).

EXAMPLE 37 Prepared as in Example 35 from 6,14-endoetheno-7-(2- hydroxy-S-methyl 2 hexyl) tetrahydrooripavine. M.P. l28129 C. Hydrochloride 265267 C. (dec.).

EXAMPLE 3 8 Prepared as in Example 35 from N-cyclopropylmethyl- 6,14-end0etheno-7-(2-hydroxy-5-methyl 2 hexyl)-tetrahydronororipavine. M.P. 263 C. (dec.). Hydrochloride 288-290 C. (dec.).

EXAMPLE 39 Prepared as in Example 35 from N-cyclopropymethyl- 6,14 endoetheno-7-(2-hydroxy-S-methyl-2-hexyl) tetranororipavine. Hydrochloride M.P. -187 C.

1 3 EXAMPLE 40 Prepared as in Example 35 from 6,l4-endoetheno-7,(1- hydroxy-l phenyl l ethyl) tetrahydrooripavine. M.P. 235 C. Hydrochloride 276-278 C. (dec.).

EXAMPLE 41 7,8-dihydro-4'-phenylcyclohex 4' en(1',2:14,8)-c0dein one and 7,8 dihydro 4' phenylcycl0hex-3'-eno (1,2:14,8)-codein0ne 6,14 endoetheno '7 (1 hydroxy-l-phenyl-l-ethyl)- tetrahydrothebaine g.) was heated with concentrated hydrochloric acid (100 ml.) and ethanol ml.) on the steam bath for 30 mins. The precipitate was collected, washed with cold water and dissolved in hot 50% aqueous ethanol. The resulting solution was basified with ammonia and the precipitated solid was collected and recrystallized from ethanol. Colorless plates, M.P. 149-151". (Found: C, 78.4; H, 6.8. C H NO requires: C, 78.6, H, 6.8%.) '7 max. 1730 cmf A sample of this product (0.363 g.) was chromatographed on a column of Merck acid washed alumina (60 g.) and developed with 200 ml. of 1% ethyl acetate in :benzene. Elution with 2% (200 m1.) and 5% ethyl acetate (600 m1.) gave 29X ml. fractions which were examined ch romatographically on thin layer plates of alumina. Separation was achieved to give 7,8-dihydro- 4' phenylcyclohex-4'-eno(1,2':14,8) codeinone (0.204 g.), M.P. 161-163" C. after recrystallization from methanol and 7,8 dihydro-4-phen ylcyclohex-3'-eno(1',2': 14, 8)-codeinone (0.020 g.). M.P 212-214" C. after recrystallization from methanol.

The mixture of isomers of the codeinone of Example 41 (M.P. 149l5l C.) was reduced with sodium borohydried (0.5 g.) in hot ethanol (200 ml.). The product was precipitated with water, collected and recrystallized four times from ethanol as white prisms. M.P. 191 C. (Found: C, 78.1; H, 7.4%. C H NO3 requires: C. 78.4; H, 7.3 Pure by thin layer chromatography.

I claim:

1. A codeine or morphine derivative selected from compounds of the formulae in which R is hydrogen or methyl,

R is methyl, ethyl, propyl, phenyl or 0-, mor p-tolyl,

R is hydrogen, cycloalkyl of 4 to 6 carbon atoms, phenyl, o-, mor p-tolyl, tetrahydrofurano, alkyl or alkenyl of up to 7 carbon atoms, or such alkyl or alkenyl of up to 7 carbon atoms substituted on any of carbon atoms 1 to 4 by cycloalkyl of 5 to 7 carbon atoms, phenyl, o-, mor p-tolyl, alkoxy of up to 3 carbon atoms, phenoxy or tetrahydrofurano, provided that R is hydrogen only when R is phenyl or o-, mor p-tolyl,

R is alkyl or alkenyl of up to 8 carbon atoms or cycloalkyl methyl of 4 to 6 carbon atoms,

R is a single oxygen atom forming part of a carbonyl group or a hydrogen atom and a hydroxy group, and

R is phenyl, o-, mor p-tolyl, and salts or bases of the above formulae with pharmaceutically acceptable, non-toxic acids.

2. A codeine or morphine derivative selected from compounds of the formula and non-toxic pharmaceutically acceptable salts thereof in which R is hydrogen or methyl, R is methyl, ethyl, propyl, phenyl or o-, mor p-tolyl, R is hydrogen, cycloalkyl of 4 to 6 carbon atoms, phenyl, o-, mor p-tolyl, tetrahydrofurano, alkyl or alkenyl of up to 7 carbon atoms, or alkyl or alkenyl of up t-o 7 carbon atoms substituted on any of carbon atoms 1 to 4 by cycloalkyl of 5 to 7 carbon atoms, phenyl, o-, mor p-tolyl, alkoxy, phenoxy or tetrahydrofurano, provided that R is hydrogen only when R is phenyl or o-, mor p-tolyl, R is alkyl or alkenyl of up to 8 carbon atoms, or cycloalkyl methyl of 4 to 6 carbon atoms. 3. A codeine or morphine derivative selected from compounds of the formula and non-toxic, pharmaceutically acceptable salts thereof in which R is hydrogen or methyl,

R is alkyl or alkenyl of up to 8 carbon atoms, or cycloalkyl methyl of 4 to 6 carbon atoms, and

R is phenyl or o-, mor p-tolyl.

4. A codeine or morphine derivative selected from compounds of the formula and non-toxic pharmaceutically acceptable salts thereof in which R is hydrogen or methyl, R is methyl, ethyl, propyl, phenyl or o-, mor p-tolyl, R is hydrogen, cycloalkyl of 4 to 6 carbon atoms, phenyl, o-, mor p-tolyl, tetrahydrofurano, alkyl or alkenyl of up to 7 carbon atoms, or alkyl or alkenyl of up to 7 carbon atoms substituted on any of carbon atoms 1 to 4 by cycloalkyl of 5 to 7 carbon atoms, phenyl, o-, mor p-tolyl, alkoxy, phenoxy or 1. 5 tetrahydrofurano, provided that R is hydrogen only when R is phenyl or mor p-tolyl,

R is alkyl or alkenyl of up to 8 carbon atoms, or

cvcloalkyl methyl of 4 to 6 carbon atoms. 5. A codeine or morphine derivative selected from compounds of the formula and non-toxic, pharmaceutically acceptable salts thereof in which R is hydrogen or methyl, R is alkyl or alkenyl of up to 8 carbon atoms, or

cycloalkyl methyl of 4 to 6 carbon atoms, and R is phenyl or 0-, mor p-tolyl.

6. A process for the production of compounds of the o R is hydrogen, cycloalkyl of 4 to 6 carbon atoms, phenyl, 0-, mor p-tolyl, tetrahydrofurano, alkyl or alkenyl of up to 7 carbon atoms, or alkyl or alkenyl of up to 7 carbon atoms substituted on any of carbon atoms 1 to 4 by cycloalkyl of 5 to 7 carbon atoms, phenyl, 0-, mor p-tolyl, alkoxy, phenoxy or tetrahydrofurano, provided that R is hydrogen only when R is phenyl or 0-, mor p-tolyl,

R is alkyl or alkenyl of up to 8 carbon atoms, or cycloalkyl methyl of 4 to 6 carbon atoms, and

R is phenyl or o-, mor p-tolyl,

which comprises reacting a compound of the formula in which R, R R and R have the meanings given above, with more than one molar equivalent 5 to 10 N- hydrochloric acid at a temperature and for a period of time suificient to bring about rearrangement of the molecule.

7. N allyl 7,8-dihydro-3-ethyl-4-methylcyclohex-3'- eno(1,2':14,8)-norcodeinone.

8. N (2 methylallyl) 7,8 dihydro 3'-n-propyl-4'- methylcyclohex-3 -eno(1,2: 14,8 -norcodeinone.

9. N cyclopropylmethyl 7,8 dihydro-3,4-dirnethylcycloheX-3-eno(1',2: 14,8 -norcodeinone.

10. N cyclobutylmethyl-7,8-dihydro-3'-ethyl-4-methylcycloheX-3 -eno(1',2: 14,8 -norcodeinone.

11. 7,8 dihydro-4-p-henylcyclohex-4'-eno(1',2:14,8)- codeinone.

References Cited FOREIGN PATENTS 937,214 9/1963 Great Britain.

ALEX MAZEL, Primary Examiner. DONALD G. DAUS, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 ,329 ,682 July 4 1967 Kenneth W. Bentley It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 46, cancel "about"; line 60, "transquilizing" should read tranquilizing Column 4, line 2, before "con-" insert an opening parenthesis; lines 4 to 6, insert a closing parenthesis same column 4 formula [0) insert an arrow from the hydrogen atom bond pointing upward toward the Column 6 between structures S and T dd three vertical lines Column 10 line 48 "H should read 1- H Column 11 line 7 before "1720" insert max. Column 12, line 44, after "max." insert 1725 line 74, "(2-hydroxy-5-methyl-Z-hexyl)" should read (Z-hydroxy-Z-pentyl) Signed and sealed this 13th day of January 1970.

(SEAL) Attest:

Edward M. Fletcher, Jr. E.

Attesting Officer Commissioner of Patents 

1. A CODEINE OR MORPHINE DERIVATIVE SELECTED FROM COMPOUNDS OF THE FORMULA: 